Rivaroxaban tablet

Abstract

The invention discloses a rivaroxaban tablet. A tablet core is prepared from the following components in parts by weight: 10 parts of rivaroxaban, 15-25 parts of meglumine, 50-80 parts of a filling agent, 20-40 parts of a disintegrating agent and 0.5-1.5 parts of a lubricating agent; wherein the particle size D90 of the rivaroxaban is 50-100 [mu] m, and the invention discloses a preparation method of the rivaroxaban tablet, and the meglumine and the rivaroxaban are adopted to form a stable clathrate compound to prepare the preparation, so that the dissolution rate and the stability of the rivaroxaban tablet can be improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a rivaroxaban tablet and a preparation method thereof. Background Art

[0002] Rivaroxaban is an anti-thrombotic drug. It is used for adult patients undergoing elective hip or knee replacement surgery to prevent venous thromboembolism (VTE). Rivaroxaban is a lipophilic drug, soluble in dimethyl sulfoxide, almost insoluble in methanol or water, and its solubility in aqueous medium is only 5-7 mg / L at 25°C, resulting in poor in vitro dissolution and very low in vivo bioavailability of its preparations. Therefore, for poorly soluble drugs, common methods to improve drug dissolution include: solid dispersion, cyclodextrin inclusion, drug micronization, solubilization with surfactants, microemulsification, preparation of liposomes, etc.

[0003] Chinese Patent with publication number CN114533899A discloses a rivaroxaban preparation and its preparation method, including rivaroxaban, cellulose, and pharmaceutically acceptable excipients. By preparing an inclusion complex intermediate and further preparing it into a preparation, the problem of poor solubility of rivaroxaban is solved. However, in this technical solution, the drug loading and encapsulation efficiency of the rivaroxaban inclusion complex are low, and the delivery efficiency of rivaroxaban is greatly reduced.

[0004] Chinese Patent with publication number CN104055743A discloses a preparation method of direct powder mixing and tableting, which solves some problems such as pitted surface, sticking to punches, loose tablets and disintegration during tableting. However, this patent does not mention whether the raw drug is micronized, and the mixing and in vitro dissolution of rivaroxaban raw materials cannot be guaranteed. Summary of the Invention

[0005] To overcome the deficiencies of the prior art, on the basis of the existing technology, the present invention screens meglumine as an inclusion material and uses the inclusion technology to provide a rivaroxaban preparation with good tableting performance, high dissolution rate and high stability. Meglumine, as an amphoteric molecule, has both hydrophilic amino groups and hydrophobic cyclic structures, and there is no report on its use for the inclusion of rivaroxaban.

[0006] Specifically, the technical solution of the present invention is as follows:

[0007] A rivaroxaban tablet, the tablet core is made of the following components in parts by weight: 10 parts of rivaroxaban, 15-25 parts of meglumine, 50-80 parts of filler, 20-40 parts of disintegrant, 0.5-1.5 parts of lubricant; wherein, the particle size D90 of the rivaroxaban is 50-100 μm.

[0008] A rivaroxaban tablet, the tablet core of which is made of the following components in parts by weight: 10 parts of rivaroxaban, 20 parts of meglumine, 65 parts of filler, 30 parts of disintegrant, and 1 part of lubricant; wherein, the particle size D90 of the rivaroxaban is 70 μm.

[0009] For the rivaroxaban tablet described above, the filler is one or more of anhydrous lactose, microcrystalline cellulose, silicified microcrystalline cellulose, hypromellose, silicic anhydride, calcium phosphate, anhydrous calcium phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium silicate, dextrin, etc.; the disintegrant is one or more of crospovidone, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, low-substituted hydroxypropyl cellulose, etc.; the lubricant is one or more of magnesium stearate, stearic acid, talc, silicon dioxide, colloidal silicon dioxide, sodium stearyl fumarate, sodium dodecyl sulfate, etc.

[0010] For the rivaroxaban tablet described above, the preparation method comprises the following steps:

[0011] (a) Dissolve rivaroxaban and meglumine in an ethanol-water mixed solvent (volume ratio 3:1), and stir to form an inclusion solution;

[0012] (b) Adjust the pH to 6.8 - 7.2, and evaporate to dryness under reduced pressure at 40 - 50 °C to obtain an inclusion complex;

[0013] (c) Mix the inclusion complex obtained in step (b) with the filler and disintegrant, granulate by wet method and then dry, add the lubricant, press into tablets, and coat, thus obtaining the product.

[0014] The present invention uses meglumine as an inclusion material to include rivaroxaban, optimizes the preparation process, solves the problem of low drug loading and encapsulation efficiency of the rivaroxaban inclusion complex in the prior art, provides a rivaroxaban tablet composed of a rivaroxaban inclusion complex with high drug loading and high encapsulation efficiency, and improves the delivery efficiency of the rivaroxaban inclusion complex. Through verification, the rivaroxaban tablet provided by the present invention has a high dissolution rate, few impurities and good stability.

[0015] Innovation of inclusion material: For the first time, meglumine and rivaroxaban are used to form a stable inclusion complex. When the weight ratio is 1.5 - 2.5:1, the inclusion rate can reach 90%, and the solubility is improved.

[0016] Synergistic effect: The basic amino group of meglumine neutralizes the acidic group of rivaroxaban, enhances the stability in the gastric juice environment, the product has a high dissolution rate and few impurities. Detailed implementation manners

[0017] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content recorded in the present invention, those skilled in the art can make various changes or modifications to the present invention, but these equivalent forms also fall within the scope defined by the appended claims of the present application.

[0018] Example 1:

[0019] Take 10 g of rivaroxaban, 20 g of meglumine, 65 g of microcrystalline cellulose, 30 g of sodium starch glycolate, and 1 g of magnesium stearate; among them, the particle size D90 of the rivaroxaban is 70 μm, and the preparation method is as follows:

[0020] (a) Dissolve rivaroxaban and meglumine in an ethanol-water mixed solvent (volume ratio 3:1), and stir to form an inclusion solution;

[0021] (b) Adjust the pH to 7.0, and evaporate to dryness under reduced pressure at 45 °C to obtain an inclusion compound;

[0022] (c) Mix the inclusion compound obtained in step (b) with microcrystalline cellulose and sodium starch glycolate, granulate by wet method and then dry, add magnesium stearate, tableting, coating, and then obtain the product.

[0023] Example 2:

[0024] Take 10 g of rivaroxaban, 25 g of meglumine, 50 g of hypromellose, 40 g of low-substituted hydroxypropyl cellulose, and 0.5 g of silicon dioxide; among them, the particle size D90 of the rivaroxaban is 100 μm, and the preparation method is as follows:

[0025] (a) Dissolve rivaroxaban and meglumine in an ethanol-water mixed solvent (volume ratio 3:1), and stir to form an inclusion solution;

[0026] (b) Adjust the pH to 6.8, and evaporate to dryness under reduced pressure at 40 °C to obtain an inclusion compound;

[0027] (c) Mix the inclusion compound obtained in step (b) with hypromellose and low-substituted hydroxypropyl cellulose, granulate by wet method and then dry, add silicon dioxide, tableting, coating, and then obtain the product.

[0028] Example 3:

[0029] Take 10 g of rivaroxaban, 15 g of meglumine, 80 g of anhydrous calcium hydrogen phosphate, 20 g of cross-linked carboxymethyl cellulose sodium, and 1.5 g of colloidal silicon dioxide; among them, the particle size D90 of the rivaroxaban is 50 μm, and the preparation method is as follows:

[0030] (a) Dissolve rivaroxaban and meglumine in an ethanol-water mixed solvent (volume ratio 3:1), and stir to form an inclusion solution;

[0031] (b) Adjust the pH to 7.2, and evaporate to dryness under reduced pressure at 50 °C to obtain the inclusion complex;

[0032] (c) Mix the inclusion complex obtained in step (b) with anhydrous calcium hydrogen phosphate and croscarmellose sodium, granulate by wet method and then dry, add colloidal silicon dioxide, tabletting, coating, and you will get the product.

[0033] Comparative Example 1:

[0034] Take 10 g of rivaroxaban, 65 g of microcrystalline cellulose, 30 g of sodium starch glycolate, and 1 g of magnesium stearate; among them, the particle size D90 of the rivaroxaban is 70 μm, and the preparation method is:

[0035] Mix rivaroxaban with microcrystalline cellulose and sodium starch glycolate, granulate by wet method and then dry, add magnesium stearate, tabletting, coating, and you will get the product.

[0036] Comparative Example 2:

[0037] Take 10 g of rivaroxaban, 20 g of meglumine, 65 g of microcrystalline cellulose, 30 g of sodium starch glycolate, and 1 g of magnesium stearate; among them, the particle size D90 of the rivaroxaban is 200 μm, and the preparation method is:

[0038] (a) Dissolve rivaroxaban and meglumine in an ethanol-water mixed solvent (volume ratio 3:1), and stir to form an inclusion solution;

[0039] (b) Adjust the pH to 7.0, and evaporate to dryness under reduced pressure at 45 °C to obtain the inclusion complex;

[0040] (c) Mix the inclusion complex obtained in step (b) with microcrystalline cellulose and sodium starch glycolate, granulate by wet method and then dry, add magnesium stearate, tabletting, coating, and you will get the product.

[0041] Comparative Example 3 (prepared according to Patent CN114533899A):

[0042] Take 12 g of rivaroxaban and dissolve it in an appropriate amount of 50 ml of dimethyl sulfoxide, and inject it into a saturated aqueous solution of 30000 Da methyl cellulose at 5 °C containing 68.4 g while stirring. Add a citric acid buffer to adjust the pH to 3.6, and stir at 5 °C for 2.5 h to obtain a red precipitate. Let it stand, filter, wash, and dry to obtain 71.0 g of rivaroxaban inclusion complex. Then take 180 g of starch, 20 g of xylitol, 10 g of low-substituted hydroxypropyl cellulose, and 10 g of magnesium stearate, and use dry granulation. Crush, sieve and mix the rivaroxaban inclusion complex, the formulated fillers, disintegrants, and lubricants respectively, and then tabletting to obtain the product.

[0043] Example 4: Drug loading and encapsulation efficiency of the rivaroxaban inclusion complex

[0044] Drug loading and encapsulation rate are the main indicators for measuring the quality of inclusion compounds. First, the weight of rivaroxaban in the encapsulated material is measured, and then the drug loading and encapsulation rate are calculated based on the drug loading, which refers to the percentage of the weight of the drug encapsulated in the inclusion compound, and the encapsulation rate, which refers to the weight percentage of the drug in the inclusion compound to the amount of feed.

[0045] Method for determining the weight of rivaroxaban in the encapsulated material:

[0046] (1) Preparation of reference solution: Weigh the rivaroxaban reference substance and add 80% methanol aqueous solution to prepare a solution containing 0.5 mg of rivaroxaban per 1 ml;

[0047] (2) Preparation of test solution: Take the inclusion compound powder containing rivaroxaban of Examples 1-3 and Comparative Examples 2-3 and add methanol to prepare a solution containing 4.25 mg of powder per 1 ml of methanol;

[0048] (3) Determination: The stationary phase of the HPLC was octadecylsilane bonded silica gel, and the mobile phase was a mixed solution of methanol and 0.01% phosphoric acid in a volume ratio of 30:70. The column temperature was 40-50°C, and the detector was an ultraviolet absorption detector with a detection wavelength of 240 nm. 10 μl of each of the reference solution and the test solution was aspirated and injected into the HPLC to read the data.

[0049] Table 1 Drug loading and encapsulation efficiency of inclusion complexes containing rivaroxaban

[0050] Group Drug loading (%) Entrapment efficiency (%) Rivaroxaban inclusion complex of Example 1 25.65 91.54 Rivaroxaban inclusion complex of Example 2 24.98 90.98 Rivaroxaban inclusion complex of Example 3 25.12 91.32 Rivaroxaban inclusion complex of Comparative Example 2 24.56 89.65 Rivaroxaban inclusion complex of Comparative Example 3 17.97 82.79

[0051] Compared with the drug loading and encapsulation efficiency of the rivaroxaban inclusion compound disclosed in Chinese patent CN114533899 A in comparative example 3, the rivaroxaban inclusion compounds prepared in Examples 1-3 of the present invention have high quality and stability, high drug loading, and an encapsulation efficiency of more than 90%, which greatly improves the efficiency of the inclusion compound in delivering the active ingredient rivaroxaban, and has significant progress. The drug loading and encapsulation efficiency of the rivaroxaban inclusion compound in comparative example 2 do not change much, indicating that the particle size has little effect. In short, meglumine and rivaroxaban can form a stable inclusion compound.

[0052] Example 5: Tableting Investigation

[0053] Table 2 Effect of tableting conditions

[0054] Group Compressibility Tablet surface Example 1 Good Smooth Example 2 Good Smooth Example 3 Good Smooth Comparative Example 1 Fair Severely defective Comparative Example 2 Good Severely defective Comparative Example 3 Fair Severely defective

[0055] The above results show that in Examples 1 - 3 provided by the present invention, meglumine is contained in the formulation, and the mass ratios of meglumine, the main drug, and other excipients are controlled. The tablets prepared have no signs of sticking to the punch, the tablet surface is smooth, and the compressibility is good. The tablets prepared in other comparative examples all have problems in the above aspects. Among them, in Comparative Example 1, rivaroxaban was mixed with microcrystalline cellulose and sodium starch glycolate, granulated by wet method and then dried, magnesium stearate was added, and then tableted. And for the rivaroxaban tablets prepared by the method disclosed in Chinese Patent CN114533899 A in Comparative Example 3, sticking to the punch and non - smooth surface occurred, and the effects were far worse than those of Examples 1 - 3. In Comparative Example 2, the particle size of rivaroxaban became larger, and many problems such as serious defects on the tablet surface also occurred.

[0056] Example 6: Dissolution determination of rivaroxaban tablets

[0057] Chromatographic conditions: Determined according to the high - performance liquid chromatography method (Appendix Ⅴ D, Part Ⅱ of Chinese Pharmacopoeia 2010 Edition). Octadecylsilane chemically bonded silica gel was used as the filler; acetonitrile - water (40:60) was used as the mobile phase; the detection wavelength was 250 nm; the column temperature was 40 °C.

[0058] Dissolution determination method: Take the samples of Examples 1 - 3 and Comparative Examples 1 - 3. According to the dissolution determination method (the second method in Appendix Ⅹ C, Part Ⅱ of Chinese Pharmacopoeia 2010 Edition), using 900 ml of acetate buffer solution (take 2.99 g of sodium acetate, place it in 1000 ml of water, add 1.66 ml of glacial acetic acid and 20 ml of 10% SDS solution, adjust the pH value to 4.50 ± 0.1 with sodium hydroxide or glacial acetic acid) as the dissolution medium, the rotation speed was 75 revolutions per minute. Operate according to the law. At 5 min, take an appropriate amount of the solution, filter it, and take the subsequent filtrate as the test solution. Separately, take about 27.5 mg of rivaroxaban reference substance, accurately weigh it, place it in a 50 - ml volumetric flask, add an appropriate amount of acetonitrile and ultrasonically dissolve it, cool it to room temperature, dilute it to the scale, shake it well, accurately measure an appropriate amount, and dilute it with the dissolution medium to prepare a solution containing about 11 μg per 1 ml as the reference solution. Accurately measure 10 μl of the test solution and the reference solution respectively, inject them into the liquid chromatograph, record the chromatogram, and calculate the dissolution amount of each tablet by the external standard method based on the peak area. The results are shown in Table 3.

[0059] Table 3 Dissolution determination results of rivaroxaban tablets in each example

[0060] Group Results at 0 day (%) Results after 6 months of accelerated testing at 40 °C, 75% RH (%) Example 1 99.2 98.7 Example 2 99.9 98.3 Example 3 100.9 99.1 Comparative Example 1 89.4 82.9 Comparative Example 2 99.8 97.1 Comparative Example 3 75.8 64.3

[0061] As can be seen from the table, the dissolution of Examples 1 to 3 of the present invention is rapid, and there is basically no change in dissolution after 6 months of acceleration at 40°C and 75% RH. In Comparative Example 1, rivaroxaban was mixed with microcrystalline cellulose and sodium starch glycolate, granulated by wet granulation and then dried, magnesium stearate was added, tableted, and coated. Since the raw materials could not be fully dissolved in the solvent, the dissolution was slow. In Comparative Example 2, the particle size of rivaroxaban increased, which had a certain impact on the dissolution rate. In Comparative Example 3, a clathrate was prepared using dimethyl sulfoxide and methylcellulose and granulated by dry granulation. During the dissolution determination, the drug precipitated and the dissolution of the tablets was poor, indicating that the preparation of the formulation by forming a stable clathrate of meglumine and rivaroxaban could improve the dissolution of the rivaroxaban tablets of the present invention.

[0062] Example 7: Determination of related substances of rivaroxaban tablets

[0063] Chromatographic conditions: Using octadecylsilane-bonded silica gel as the filler, 5 mmol / L phosphoric acid solution as mobile phase A, 5 mmol / L phosphoric acid solution - acetonitrile (10:90) as mobile phase B, and perform linear gradient elution according to the following table; the detection wavelength is 250 nm; the column temperature is 35°C. See Table 4.

[0064] Table 4 High-performance liquid chromatography mobile phase conditions

[0065] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 80 20 25 50 50 25.1 80 20 30 80 20

[0066] Determination method: Take an appropriate amount of the fine powder of the samples of Examples 1-3 and Comparative Examples 1-3 (equivalent to about 50 mg of rivaroxaban), weigh accurately, place it in a 50 ml volumetric flask, add 40 ml of 50% acetonitrile solution, ultrasonically treat for 15 minutes, cool to room temperature, dilute to the mark with 50% acetonitrile solution, shake well, filter, and take the subsequent filtrate as the test solution; accurately measure 0.2 ml, place it in a 100 ml volumetric flask, dilute to the mark with 50% acetonitrile solution, shake well, as the control solution; take 5 μl of the control solution and inject it into the liquid chromatograph, adjust the detection sensitivity to make the peak height of the main component chromatographic peak 10% of the full scale. Then accurately measure 5 μl of the test solution and the control solution respectively, inject them into the liquid chromatograph, and record the chromatogram. If there are impurity peaks in the chromatogram of the test solution, except for the excipient peaks, the area of a single impurity peak shall not be greater than 0.75 times (0.15%) of the main peak area of the control solution, and the total amount of impurities shall not be greater than 3 times (0.6%) of the main peak area of the control solution. The results are shown in Table 5.

[0067] Table 5 Contents of rivaroxaban and related substances in rivaroxaban tablets of each example

[0068]

[0069] The results of the content and total related substances of the rivaroxaban tablets prepared in Examples 1-3 after being placed for 6 months under accelerated conditions showed that there was no difference in the labeled content of this product compared with that at day 0. The dissolution at day 0 was greater than 98%, with rapid drug release. Moreover, there was no significant difference in the dissolution after being placed for 6 months under accelerated conditions compared with that at day 0, and it was all greater than 98%. In addition, the total related substances of this product did not exceed 0.5% of the labeled amount after being placed for 6 months under accelerated conditions. The above results indicated that the labeled content and dissolution of this product had good stability. For Comparative Example 1 and Comparative Example 3 at day 0, the main drug contents were 98.7% and 99.5% respectively, and the related substances were 0.67% and 0.93% respectively. After being placed for 6 months under accelerated conditions, the main drug contents were 87.9% and 82.3% respectively, and the related substances were 1.09% and 1.34% respectively, indicating that the rivaroxaban tablets were unstable under accelerated conditions. In Comparative Example 2, the particle size of rivaroxaban increased. At day 0, the main drug content was 99.1% and the related substances were 0.42%. After being placed for 6 months under accelerated conditions, the main drug content was 98.4% and the related substance was 0.51%, which had little impact on the content and related substances. It was shown that preparing the preparation by forming a stable inclusion complex of meglumine and rivaroxaban could improve the stability of the rivaroxaban tablets of the present invention.

[0070] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A rivaroxaban tablet, characterized in that, The tablet core is made of the following components in parts by weight: 10 parts of rivaroxaban, 15 - 25 parts of meglumine, 50 - 80 parts of filler, 20 - 40 parts of disintegrant, 0.5 - 1.5 parts of lubricant; wherein, the particle size D90 of the rivaroxaban is 50 - 100 μm.

2. The rivaroxaban tablet according to claim 1, characterized in that, The tablet core is made of the following components in parts by weight: 10 parts of rivaroxaban, 20 parts of meglumine, 65 parts of filler, 30 parts of disintegrant, 1 part of lubricant; wherein, the particle size D90 of the rivaroxaban is 70 μm.

3. The rivaroxaban tablet according to claim 1 or 2, characterized in that, The filler is one or more of anhydrous lactose, microcrystalline cellulose, siliconized microcrystalline cellulose, hypromellose, silicic anhydride, calcium phosphate, anhydrous calcium phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium silicate, dextrin, etc.; the disintegrant is one or more of crospovidone, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, low-substituted hydroxypropyl cellulose, etc.; the lubricant is one or more of magnesium stearate, stearic acid, talc, silicon dioxide, colloidal silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, etc.

4. The rivaroxaban tablet according to claim 1 or 2, characterized in that, The filler is microcrystalline cellulose, the disintegrant is sodium starch glycolate, and the lubricant is magnesium stearate.

5. The rivaroxaban tablet according to claim 1 or 2, characterized in that, The filler is hypromellose, the disintegrant is low-substituted hydroxypropyl cellulose, and the lubricant is silicon dioxide.

6. The rivaroxaban tablet according to claim 1 or 2, characterized in that, The filler is anhydrous calcium hydrogen phosphate, the disintegrant is croscarmellose sodium, and the lubricant is colloidal silicon dioxide.

7. The rivaroxaban tablet according to claim 1 or 2, characterized in that, The preparation method comprises the following steps: (a) Dissolve rivaroxaban and meglumine in an ethanol-water mixed solvent (volume ratio 3:1), and stir to form an inclusion solution; (b) Adjust the pH to 6.8 - 7.2, and evaporate to dryness under reduced pressure at 40 - 50 °C to obtain an inclusion complex; (c) Mix the inclusion complex obtained in step (b) with the filler and disintegrant, granulate by wet method and then dry, add the lubricant, press into tablets, and coat, thus obtaining the product.

8. The rivaroxaban tablet according to claim 7, characterized in that, The preparation method comprises the following steps: (a) Dissolve rivaroxaban and meglumine in an ethanol-water mixed solvent (volume ratio 3:1), and stir to form an inclusion solution; (b) Adjust the pH to 7.0, and evaporate to dryness under reduced pressure at 45 °C to obtain an inclusion complex; (c) Mix the inclusion complex obtained in step (b) with the filler and disintegrant, granulate by wet method and then dry, add the lubricant, press into tablets, and coat, thus obtaining the product.

9. The rivaroxaban tablet according to claim 7, characterized in that, The preparation method comprises the following steps: (a) Dissolve rivaroxaban and meglumine in an ethanol-water mixed solvent (volume ratio 3:1), and stir to form an inclusion solution; (b) Adjust the pH to 6.8, and evaporate to dryness under reduced pressure at 50 °C to obtain an inclusion complex; (c) Mix the inclusion complex obtained in step (b) with the filler and disintegrant, granulate by wet method and then dry, add the lubricant, press into tablets, and coat, thus obtaining the product. The rivaroxaban tablet according to claim 7, characterized in that, The preparation method comprises the following steps: (a) Dissolve rivaroxaban and meglumine in an ethanol-water mixed solvent (volume ratio 3:1), and stir to form an inclusion solution; (b) Adjust the pH to 7.2, and evaporate to dryness under reduced pressure at 40 °C to obtain an inclusion complex; (c) Mix the inclusion complex obtained in step (b) with the filler and disintegrant, granulate by wet method and then dry, add the lubricant, press into tablets, and coat, thus obtaining the product.

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